. We demonstrated that muscle-derived stem/progenitor cells (MDSPCs) isolated from the skeletal muscle of naturally aged wild-type (WT) mice and mice that model a human progeroid syndrome (ERCCI-deficient mice) are defective in proliferation, multi-lineage differentiation and tissue regeneration after injury. This is consistent with the notion that autonomous defects in the adult stem cell compartment, which accrue over time, contribute to the loss of tissue regeneration and homeostasis associated with normal and accelerated aging. However, there is also evidence that aging and disease affects the stem cell niche, impacting stem cell function via non-autonomous mechanisms. In addition, there is strong evidence that factors circulating in the serum of aged mice affect stem/progenitor cell function. Therefore, it remains unclear if aging-related loss of adult stem cell function is primarily driven by cell autonomous and/or non-autonomous mechanisms. Thus one goal of this project is to characterize the mechanism through which MDSPCs become dysfunctional with aging using mouse models of tissue- and cell type-specific inactivation of ERCCI. The proposed experiments will determine if stochastic, endogenous damage directly or indirectly drives stem cell dysfunction. We also demonstrated that intraperitoneal administration of MDSPCs isolated from young WT mice into ERCCI-deficient mice results in a significant lifespan and healthspan extension, as well as increased tissue regeneration and neovascularization. This occurred via a paracrine/endocrine mechanism as donor cells were not detected in all tissues in which benefits were seen. Thus a second goal of this project is to characterize this paracrine/endocrine mechanism by which young MDSPCs promote health and longevity when delivered systemically. Finally we will identify the factors secreted by young, functional stem cells that are important for conferring their beneficial effects. The successful completion ofthe proposed studies should lead to novel mechanistic information about the contribution of stem cells to maintaining healthspan and therapeutic stem cell-based approaches to improve human aging.